Inflammation and vascular hyperpermeability have been shown to play an important role in the development of cardiovascular diseases, especially atherosclerosis. We are currently exploring innovative approaches to block vascular inflammation and enhance vascular stability. In this regard, we have shown that the novel protein Slit2 inhibits CCL2-induced chemotaxis of monocytes. Furthermore, we have shown that Slit2 inhibits lipopolysaccharides (LPS)-induced changes in proteins that promote vascular stability in endothelial cells. Our central hypothesis is that Slit2 will have a broad-based effect in inhibiting monocyte chemotaxis/transendothelial migration, leukocyte endothelial interaction and vascular permeability. These processes are important during the development of atherosclerosis. Exploring how Slit2 affects vascular dysfunction is of fundamental importance for developing novel therapies against various inflammatory disorders, including atherosclerosis. To this end, we will use an innovative, multi-disciplinary approach to analyze the anti-inflammatory/permeability properties of Slit2. First, we will analyze the effect of Slit2 on inflammation and vascular permeability in vitro and in vivo using a transgenic mouse model system expressing yellow fluorescent protein (YFP) in response to inflammatory stimuli, especially LPS and chemokine CCL2. Furthermore, we will map the region of Slit2 that possesses the anti-chemotactic/inflammatory properties and promotes vascular stability. Additionally, we will determine the clinical utility of the Slit2 molecule to prevent LPS and diet-induced atherosclerosis in ApoE-/- mouse model systems. These studies will provide novel rationales and concepts for the development of Slit2 as a therapeutic strategy for inflammatory disorders, such as atherosclerosis. Ultimately, insight gained from our proposed studies may help us to explore new translational approaches to combat atherosclerosis.